Molecular Tweezers Targeting Transthyretin Amyloidosis

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Ferreira, N (Author) Other; Pereira Henriques, A (Author) Other; Attar, A (Author) Other; Klaerner, FG (Author) Other; Schrader, T (Author) Other; Bitan, G (Author) Other; Luis Gales (Author) ICBAS; Maria Joao Saraiva (Author) ICBAS; Almeida, MR (Author) ICBAS

Journal

Title: Neurotherapeutics

Vol. 11

Pages: 450-461

ISSN: 1933-7213

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 35 Citations

Scopus - 38 Citations

Other information

Authenticus ID: P-009-D5W

DOI: 10.1007/s13311-013-0256-8

Abstract (EN): Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12